Study information

Scientific title

Acronym

A-WOL LF

Study hypothesis

1. To refine existing regimes of drugs with known activity against Wolbachia (doxycycline, rifampicin):1.1. To provide a shortened treatment period compared to the "gold-standard" (200 mg doxycycline per day for 4 weeks) using the combination of doxycycline and rifampicin1.2. To provide a reduction of the daily dosage of doxycycline from 200 mg to 100 mg2. To verify an ameliorating effect of doxycycline and the combination of doxycycline and rifampicin on the dilation of supratesticular lymphatic vessels (i.e. subclinical lymphatic pathology) using the different drug regimes

As of 01/12/2009 an additional follow-up timepoint after 18 months was approved by all three ethics committees for the secondary outcomes. Please see the secondary outcome measures section below for more details.

Ethics approval

Ethical clearances have been obtained from the Committee on Human Research Publication and Ethics, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana (approved 16th April 2008), from the Ethical Committee, University Clinic Bonn, Faculty of Medicine, Bonn, Germany (approved 18th March 2008) and from the Research Ethics Committee, Liverpool School of Tropical Medicine, Liverpool, UK (approved 26th March 2008).

Study design

Randomised double-blind placebo-controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Lymphatic filariasis (Wuchereria bancrofti)

Intervention

The participants are randomised and assigned to one of the following seven treatment regimens:

Intervention type

Drug

Phase

Phase II/III

Drug names

Doxycycline, rifampicin

Primary outcome measures

Current primary outcome measures as of 08/11/2012 (protocol change approved by the DMEC of this trial on 02/03/2011, before de-blinding on 24/05/2011):Macrofilaricidal effect of the different treatment arms verified as absence of worm nests (Filaria Dance sign [FDS]; adult filariae in dilated lymphatic vessels) in the supratesticular vessels detected by ultrasonography, assessed 12 months after the start of drug administration.

Previous primary outcome measures until 08/11/2012:Macrofilaricidal effect of the different treatment arms assessed by reduction in the number of worm nests (Filaria Dance sign [FDS]; adult filariae in dilated lymphatic vessels) in the supratesticular vessels detected by ultrasonography, measured pre-treatment as well as 12 months after the start of drug administration.

For all above mentioned primary and secondary outcome measures: Treatment regimens 2 to 6 will subsequently be tested first for superiority compared to placebo (regimen 7) and second for equivalence to the standard therapy (regimen 1).

Secondary outcome measures

Current secondary outcome measures as of 08/11/2012 (protocol change approved by the DMEC of this trial on 02/03/2011, before de-blinding on 24/05/2011):1. Macrofilaricidal effect of the different treatment arms verified as absence of FDS in the supratesticular vessels detected by ultrasonography, assessed 18 and 24 months after the start of drug administration2. Macrofilaricidal effect of the different treatment arms assessed by reduction in the number of FDS in the supratesticular vessels detected by ultrasonography compared to pre-treatment, determined 12, 18 and 24 months after the start of drug administration3. Macrofilaricidal effect of the different treatment arms assessed by reduction of circulating filarial antigen (CFA) levels compared to pre-treatment, measured by TropBio® ELISA and ICT card test 12, 18 and 24 months after the start of drug administration 4. Long-term sterilising effect of the female adult worms in the different treatment arms as assessed by microfilaria (mf) count (filtration method): 4.1 Reduction (%) or absence of microfilariae 4.2 Duration (months) of amicrofilaraemia 5. Reduction (%) or absence of Wolbachia ftsZ copy numbers/microfilariae compared to pre-treatment, assessed by polymerase chain reaction (PCR) 4, 12, 18 and 24 months after the start of drug administration 6. Reduction of supratesticular lymphatic vessel dilation compared to pre-treatment, measured 12, 18 and 24 months after the start of drug administration 7. Parasite specific immuno-globulin subclasses and cytokine responses, as well as other biomarkers such as vascular endothelial growth factors (VEGFs) measured pre-treatment as well as 4, 12 and 24 months after the start of drug administration

Previous secondary outcome measures as of 01/12/2009, until 08/11/2012:1. Macrofilaricidal effect of the different treatment arms assessed by reduction in the number of worm nests in the supratesticular vessels detected by ultrasonography, measured 18 and 24 months after the start of drug administration 2. Macrofilaricidal effect of the different treatment arms assessed by absence of FDS in the supratesticular vessels detected by ultrasonography, measured pre-treatment as well as 12, 18 and 24 months after the start of drug administration 3. Macrofilaricidal effect of the different treatment arms assessed by levels of antigenaemia (enzyme-linked immunosorbent assay [ELISA] test) - reduction of circulating filarial antigen [CFA]) - measured pre-treatment as well as 4, 12, 18 and 24 months after the start of drug administration 4. Long-term sterilising effect of the female adult worms in the different treatment arms as assessed by microfilaria (mf) count (filtration method) and polymerase chain reaction (PCR) analysis: 4.1. Reduction (%) or absence of microfilariae 4.2. Duration (months) of amicrofilaraemia 4.3. Reduction (%) or absence of Wolbachia ftsZ copy numbers/microfilariae assessed by PCR Measured pre-treatment as well as 4, 12, 18 and 24 months after the start of drug administration 5. Reduction of supratesticular lymphatic vessel dilation measured pre-treatment as well as 12, 18 and 24 months after the start of drug administration 6. Parasite specific immuno-globulin subclasses and cytokine responses, as well as other biomarkers such as vascular endothelial growth factors (VEGFs) measured pre-treatment as well as 4, 12, 18 and 24 months after the start of drug administration

For all above mentioned primary and secondary outcome measures: Treatment regimens 2 to 6 will subsequently be tested first for superiority compared to placebo (regimen 7) and second for equivalence to the standard therapy (regimen 1).

Initial information at time of registration:1. Macrofilaricidal effect of the different treatment arms assessed by reduction in the number of worm nests in the supratesticular vessels detected by ultrasonography, measured 24 months after the start of drug administration2. Macrofilaricidal effect of the different treatment arms assessed by absence of FDS in the supratesticular vessels detected by ultrasonography, measured pre-treatment as well as 12 and 24 months after the start of drug administration3. Macrofilaricidal effect of the different treatment arms assessed by levels of antigenaemia (enzyme-linked immunosorbent assay [ELISA] test) - reduction of circulating filarial antigen [CFA]) - measured pre-treatment as well as 4, 12 and 24 months after the start of drug administration4. Long-term sterilising effect of the female adult worms in the different treatment arms as assessed by microfilaria (mf) count (filtration method) and polymerase chain reaction (PCR) analysis:4.1. Reduction (%) or absence of microfilariae 4.2. Duration (months) of amicrofilaraemia4.3. Reduction (%) or absence of Wolbachia ftsZ copy numbers/microfilariae assessed by PCR Measured pre-treatment as well as 4, 12 and 24 months after the start of drug administration5. Reduction of supratesticular lymphatic vessel dilation measured pre-treatment as well as 12 and 24 months after the start of drug administration6. Parasite specific immuno-globulin subclasses and cytokine responses, as well as other biomarkers such as vascular endothelial growth factors (VEGFs) measured pre-treatment as well as 4, 12 and 24 months after the start of drug administration

For all above mentioned primary and secondary outcome measures: Treatment regimens 2 to 6 will subsequently be tested first for superiority compared to placebo (regimen 7) and second for equivalence to the standard therapy (regimen 1).

Overall trial start date

01/05/2008

Overall trial end date

30/04/2011

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 08/11/2012 (protocol change approved by the DMEC of this trial on 02/03/2011):1. Men aged between 18 - 50 years2. Good general health without any clinical condition requiring long-term medication and with normal renal and hepatic laboratory profiles3. Body weight (BW): ≥40kg4. Presence of at least one scrotal worm nest detected by ultrasonography

Participant type

Patient

Age group

Adult

Gender

Male

Target number of participants

299

Participant exclusion criteria

1. Known intolerance to the study drugs (doxycycline, rifampicin), or to ivermectin and/or albendazole2. History of severe allergic reaction or anaphylaxis3. History of alcohol or drug abuse4. Anti-filarial therapy within the last 10 months5. Evidence of clinically significant neurological, cardiac, pulmonary, hepatic, metabolic, rheumatologic or renal disease as far as it can be assessed by history of participants, physical examination, and/or laboratory examinations including blood and urine analysis6. Laboratory evidence of liver disease (alanine aminotransferase [ALT], gamma-glutamyl transferase [gamma-GT] greater than 1.25 times the upper limit of normal results as stated by the manufacturer of dipstick tests, Roche®)7. Laboratory evidence of renal disease (serum creatinine greater than 1.25 times the upper limit of normal results as stated by the manufacturer of dipstick tests, Roche®)8. Laboratory evidence of diabetes (urine dipstick chemistry)9. Behavioural, cognitive or psychiatric disease that in the opinion of the trial clinician affects the ability of the participant to understand and comply with the study10. Severe asthma or respiratory disease (emergency room visit or hospitalisation)11. Undergone splenectomy12. Participation in other drug trials concurrent with this study13. Any other condition that, in the opinion of the investigator (trial clinician), would risk the safety or rights of a participant in the trial or would render the subject unable to comply with the protocol